There is now a body of evidence that metalloproteinases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. In addition metalloproteinases have been shown to be involved in the processing of cell surface proteins that have been implicated in a number of diseases, including inflammatory disorders.
Tumor necrosis factor alpha (TNF-.alpha.) is a cell associated cytokine that is processed from a 26 kd precursor form to a 17 kd active form. TNF-.alpha. has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF-.alpha. has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF-.alpha. with specific antibodies can be beneficial in a variety of circumstances including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet, 1994, 344, 1105) and non-insulin dependent diabetes melitus. (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22) and Crohn's disease (MacDonald T. et al. Clin. Exp. Immunol. 81, 1990, 301).
Compounds which inhibit the production of TNF-.alpha. are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently it has been shown that a matrix metalloproteinase (MMP) or family of metalloproteinases, hereafter known as TNF-convertases (TNF-C), as well as other MP's are capable of cleaving TNF-.alpha. from its cell associated to soluble form (Gearing et al Nature, 1994, 370, 555). This invention describes molecules that inhibit this conversion and hence the secretion of active TNF-.alpha. a from cells.
The compounds of the current invention inhibit the production of TNF-.alpha. from cells stimulated with LPS. Furthermore, some of the present compounds are selective for TNF-C inhibition over matrix metalloproteinases. This selectivity offers a distinct advancement over compounds of the current art, because non-selective MMP inhibitors have been found to produce toxic manifestations related to tendonitis and fibroplasia in clinical trials.
The compounds of the current invention do not inhibit MMPs at concentrations expected to produce a therapeutically positive response through the inhibition of TNF. The compounds of the present invention are therefore expected to be safer to patients taking the drug because of their selective inhibition profile for soluble TNF-.alpha. production.
The present novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrom, post ischaemic reperfusion injury, malaria, Crohn's disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, osteo and rheumatoid arthritis, multiple sclerosis, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV, neuro-denerative diseases and non-insulin dependent diabetes melitus.
Since excessive TNF-.alpha. production has been noted in several disease conditions also characterized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF-.alpha. production may also have a particular advantage in diseases where both mechansisms are involved.
EP 0,780,386 describes MMP inhibitors of formula A: ##STR2##
wherein Y can be NHOH, R.sup.1 and R.sup.2 can combine to form a cycloalkyl or heterocyclo alkyl group, R.sup.3 and R.sup.4 can be a variety of groups including H, and R.sup.5 can be substituted aryl. EP 0,780,386 does not disclose any compounds wherein Ar is a disubstituted phenyl or pyridyl or a bicyclic heteroaryl group.
The compounds of the current invention act as inhibitors of MPs, that process TNF-.alpha.. These novel molecules are provided as anti-inflammatory compounds and cartilage protecting therapeutics. The inhibiton of TNF-C, and other metalloproteinases by molecules of the present invention indicates they are anti-inflammatory.